Dry eye disease, in the meaning of this invention, relates to any condition relating to ocular dryness and/or tear deficiency, including but not limited to conditions related to a pathological evaporation of fluid from the cornea surface, or conditions related to defective tear film, or more generally any corneal or conjunctive dryness, which can be due to insufficient production of tears, and the conditions resulting therefrom, such as corneal keratitis or corneal epithelium erosion. For example keratoconjunctivis sicca (KCS), atopic keratoconjunctivitis sicca (AKC) and vernal keratoconjunctivitis (VKC) are dry eye diseases.
Cyclosporines are a large class of peptide compounds having various pharmaceutical applications, such as immunosuppressant and anti-inflammatory applications. Cylosporines include cyclosporine A, B, C and D. The most widely investigated cyclosporin is cyclosporin A and cyclosporine A derivatives. Other common immunosuppressive agents are sirolimus or tacrolimus and their derivatives.
Cyclosporine oil-in-water ophthalmic emulsions have been described, and among them the emulsions commercialized by Allergan under the trademark name Restasis® (cyclosporine ophthalmic emulsion 0.05%).
U.S. Pat. No. 4,839,342 describe the use of cyclosporin for the treatment of immune keratoconjunctivis sicca (KCS), and a method of increasing tear production for a tear-deficient eye, in particular directed to a patient suffering from a immune mediated dysfunction of lacrimal glands. The method disclosed in this patent includes administering cyclosporine, preferably cyclosporine A, with a pharmaceutical excipient being olive oil, arachis oil, castor oil or mineral oil.
Shulin Ding and Orest Olejnik have published a poster in the AAPS annual meeting on Nov. 3, 1997; this document relates to castor oil-based oil-in-water emulsions using 0.1 to 0.4% cyclosporine and having a weight ratio cyclosporine/oil of 0.08. This poster discloses that the concentration in cyclosporine A in the oil is optimized at the level of 7.4% w/w which is below the solubility of the cyclosporine in the specific oil vehicle castor oil (10% w/w).
WO02005/032577 describes a method for treating an eye of a human comprising administering an emulsion comprising less than 0.1% cyclosporine and having a weight ratio cyclosporine/castor oil of less than 0.08.
Although this above cited patent application describes further oils, it is not obvious to one skilled in the art that cyclosporine will have the same behaviour in any oily vehicle, because it does not have the same solubility in all oils, and the bioavailability of the cyclosporine in one oily vehicle does not give information on its bioavailability in another oily vehicle.
An emulsion is a system consisting of two immiscible liquid phases, one of which, in fine droplets, is dispersed throughout the other, the system being stabilized by a third component, the emulsifying agent. Emulsions are inherently unstable, and emulsifiers are essential for both their initial formation and long-term stability.
Due to their small droplet size, submicronic or nano-emulsions may appear transparent, and Brownian motion prevents sedimentation or creaming, hence offering increased stability.
The instability of an emulsion will appear as phase separation due to creaming (density differences), Ostwald ripening (disproportionation) flocculation (aggregation through interparticle collision), and coalescence (fusion of separate droplets). An important distinction is that flocculation is often reversible while coalescence is not. The process of droplet coalescence is the normal way in which an emulsion coarsens with time, i.e. the mean particle size of the droplet increases upon storage.
Presence of larger aggregates promotes faster creaming and thus facilitates coalescence. This is especially true for polydisperse systems where different creaming rates produce enhanced droplet encounter rates. As a consequence, the droplet size distribution of an emulsion governs emulsion properties such as long-term stability.
Therefore, a monomodal droplet population has the benefits of increased stability besides of the drug content uniformity which is essential in pharmaceutical applications for the administration of a correct drug dose.
Even though the prior art formulations, such as Restasis®, are currently useful to treat conditions for which few treatment are available, it is known that the bioavailability of the prior art formulations is not optimal, and one of the known drawbacks of Restasis®, for example, is that it may take several weeks to take full effect. In addition, castor oil-based cyclosporine emulsion such as Restasis® presents a bimodal droplet population (Ding, abstract AAPS 1997). Such formulation is expected to have decreased shelf life as a result of the coalescence of the oil droplets.
There is therefore still a need for alternative solutions for treating dry eye conditions, with emulsions having at least the same physico-chemical stability properties and improved bioavailability of the drug. In the sense of this invention, bioavailability means the percentage of drug that can be detected in the target ocular tissue after its administration. Detection of the drug can be accomplished pharmacodynamically (quantification of a biological response to the cyclosporine) or pharmacokinetically (quantification of actual drug concentration).
Moreover, patients suffering from dry eye diseases have very sensitive eyes, and it is an objective of this invention to provide a composition providing comfort as well as therapy.